The aberrant fusion proteins PML-RAR alpha and PLZF-RAR alpha contribute to the overexpression of cyclin Al in acute promyelocytic leukemia

Cyclin A1 is a newly discovered cyclin that is overexpressed in certain mye loid leukemias. Previously, the authors found that the frequency of cyclin A1 overexpression is especially high in acute promyelocytic leukemia (APL). In this study, the authors investigated the mechanism of cyclin A1 overexp ression in APL cells and showed that the APL-associated aberrant fusion pro teins (PML-retinoic acid receptor alpha [PML-RAR alpha] or PLZF-RAR alpha) caused the increased levels of cyclin A1 in these cells. The ectopic expres sion of either PML-RAR alpha or PLZF-RAR alpha in U937 cells, a non-APL mye loid cell line, led to a dramatic increase of cyclin A1 messenger RNA and p rotein, This elevation of cyclin A1 was reversed by treatment with all-tran s retinoic acid (ATRA) in cells expressing PML-RAR alpha but not PLZF-RAR a lpha. ATRA also greatly reduced the high levels of cyclin Al in the APL cel l lines NB4 and UF-1. No effect of ATRA on cyclin Al levels was found in th e ATRA-resistant NB4-R2 cells. Further studies using ligands selective for various retinoic acid receptors suggested that cyclin A1 expression is nega tively regulated by activated RAR alpha. Reporter assays showed that PML-RA R alpha led to activation of the cyclin A1 promoter. Addition of ATRA inhib ited PML-RAR alpha -induced cyclin A1 promoter activity. Taken together, ou r data suggest that PML-RAR alpha and PLZF-RAR alpha cause the high-level e xpression of cyclin Al seen in acute promyelocytic leukemia, (C) 2000 by Th e American Society of Hematology.